Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage. Persistent DNA lesions in tissue-resident macrophages with XPF-ERCC1 DNA repair defects lead to neuroinflammation and neuronal cell death in mice. Microglia accumulate dsDNA and chromatin fragments in the cytosol, which stimulate a viral-like immune response in Er1^Cx/- and naturally aged murine brains. Cytosolic DNAs are packaged into extracellular vesicles (EVs) released from microglia, which discharge their dsDNA cargo into IFN-responsive neurons, triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, targeting EVs deliver recombinant DNase I to Er1^Cx/- brain microglia in vivo. This approach prevents neuroinflammation, reduces neuronal apoptosis, and delays neurodegenerative symptoms in Er1^Cx/- mice. The study reveals a causal mechanism for neuroinflammation and provides a therapeutic strategy against age-related neurodegeneration. DNA damage and neurodegenerative disorders are closely linked, with DNA damage driving inflammation and cellular malfunction. Microglia, the resident immune cells of the CNS, become chronically activated in the presence of DNA damage, leading to neuroinflammation and neurodegeneration. XPF-ERCC1 is crucial for DNA repair, and its deficiency leads to premature aging and neurodegeneration. The study shows that microglia in Er1^Cx/- mice accumulate cytosolic DNA, triggering a type-I IFN response and neuronal cell death. EVs from these microglia carry dsDNA and target IFN-responsive neurons, causing apoptosis. Targeting EVs with DNase I reduces cytosolic DNA, inflammation, and neurodegeneration. The findings highlight the role of DNA damage in neurodegeneration and suggest a therapeutic strategy using EVs to deliver DNase I.Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage. Persistent DNA lesions in tissue-resident macrophages with XPF-ERCC1 DNA repair defects lead to neuroinflammation and neuronal cell death in mice. Microglia accumulate dsDNA and chromatin fragments in the cytosol, which stimulate a viral-like immune response in Er1^Cx/- and naturally aged murine brains. Cytosolic DNAs are packaged into extracellular vesicles (EVs) released from microglia, which discharge their dsDNA cargo into IFN-responsive neurons, triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, targeting EVs deliver recombinant DNase I to Er1^Cx/- brain microglia in vivo. This approach prevents neuroinflammation, reduces neuronal apoptosis, and delays neurodegenerative symptoms in Er1^Cx/- mice. The study reveals a causal mechanism for neuroinflammation and provides a therapeutic strategy against age-related neurodegeneration. DNA damage and neurodegenerative disorders are closely linked, with DNA damage driving inflammation and cellular malfunction. Microglia, the resident immune cells of the CNS, become chronically activated in the presence of DNA damage, leading to neuroinflammation and neurodegeneration. XPF-ERCC1 is crucial for DNA repair, and its deficiency leads to premature aging and neurodegeneration. The study shows that microglia in Er1^Cx/- mice accumulate cytosolic DNA, triggering a type-I IFN response and neuronal cell death. EVs from these microglia carry dsDNA and target IFN-responsive neurons, causing apoptosis. Targeting EVs with DNase I reduces cytosolic DNA, inflammation, and neurodegeneration. The findings highlight the role of DNA damage in neurodegeneration and suggest a therapeutic strategy using EVs to deliver DNase I.